rs794727741

Variant names:

• chr20-63442521-G-A
• rs794727741
• NM_172107.4:c.701C>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_172107.4(KCNQ2):​c.701C>T​(p.Thr234Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.77

Genes affected

KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a transmembrane_region Helical; Name=Segment S5 (size 20) in uniprot entity KCNQ2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCNQ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. Gene score misZ: 4.0411 (above the threshold of 3.09). Trascript score misZ: 3.6968 (above the threshold of 3.09). GenCC associations: The gene is linked to seizures, benign familial neonatal, 1, neonatal-onset developmental and epileptic encephalopathy, benign familial neonatal-infantile seizures, benign neonatal seizures, malignant migrating partial seizures of infancy, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, developmental and epileptic encephalopathy, 7, benign familial infantile epilepsy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 20-63442521-G-A is Pathogenic according to our data. Variant chr20-63442521-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 197892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4	c.701C>T	p.Thr234Ile	missense_variant	Exon 5 of 17	ENST00000359125.7	NP_742105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7	c.701C>T	p.Thr234Ile	missense_variant	Exon 5 of 17	1	NM_172107.4	ENSP00000352035.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Jun 27, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an individual with seizures and developmental delay, though parental segregation was not included (PMID: 29056246); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S5; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25818041, 29720203, 29056246) -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Oct 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 234 of the KCNQ2 protein (p.Thr234Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of epilepsy (PMID: 29056246, 29720203; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 197892). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ2 protein function with a positive predictive value of 95%. This variant disrupts the p.Thr234 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ2-related conditions (PMID: 25818041; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy, 7 Pathogenic:1

Aug 01, 2024

Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.701C>T, p.Thr234Ile, variant found is located in exon 5 of the KCNQ2 gene. This variant is reported in ClinVar (rs794727741) classified as pathogenic and in this same database it is reported de novo with no family history of the pathology (ClinVar: VCV000197892.16) (PMID:29056246) (PS2). The variant is located in a functional domain of the protein (PM1). Other variants in the same amino acid position (p.Thr234Pro, p.Thr234Ala) have been described and classified as pathogenic (PMID:25818041; PMID:29720203) (PM5). The variant found is not present in population databases such as GnomAD, ExAc or 1000 genomes (PM2_Supporting). Missense variants are a frequent cause of pathogenicity in this gene, with 362 pathogenic variants described and only 25 benign (PP2). Bioinformatics predictors classify this variant as deleted (PP3). A 6-year-old patient with intellectual disability presented seizures from the second day of life that were refractory to treatment. -

Seizure Pathogenic:1

Dec 05, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;.;T;T;D;T;D;T;.;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;M;.;M;M;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	.;.;.;.;D;.;D;.;D;D;D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;D;D;D;D;D;D
Polyphen		0.68	P;.;.;.;.;.;P;.;P;P;.;.
Vest4		0.95
MutPred		0.58		Loss of ubiquitination at K230 (P = 0.0573);Loss of ubiquitination at K230 (P = 0.0573);Loss of ubiquitination at K230 (P = 0.0573);Loss of ubiquitination at K230 (P = 0.0573);Loss of ubiquitination at K230 (P = 0.0573);.;Loss of ubiquitination at K230 (P = 0.0573);.;Loss of ubiquitination at K230 (P = 0.0573);Loss of ubiquitination at K230 (P = 0.0573);Loss of ubiquitination at K230 (P = 0.0573);.;
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.89
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794727741; hg19: chr20-62073874; COSMIC: COSV60432606; COSMIC: COSV60432606;